Abstract: Individuals vary widely in drug response. The enormous microbial communities (microbiota) in the human gastrointestinal tract have been shown to influence drug metabolism at multiple levels, but we cannot currently predict whether an individual's microbiota predisposes them towards efficient or inefficient metabolism of any drug. Attempts to examine the connections between interpersonal differences in gut microbial community composition and individual response to drug therapy have been nearly impossible due to the lack of tractable in vivo models that capture the microbial community variation that exists between humans. Solutions to these challenges could have a profound and rapidly translatable impact on medical therapy because an understanding of how an individual's microbiota determines drug pharmacokinetics could guide drug prescription, routes of administration, and dosage. Unlike polymorphisms in our human genomes, gut microbial community composition can be rapidly modified, opening the door to new approaches in personalized medicine in which both sides of the patient-drug interaction are optimized for maximum benefit. This proposal describes a novel approach for measuring the connections between interpersonal differences in microbial community composition and drug response: we will transplant gut microbial communities, captured at multiple timepoints, from a large cohort of unrelated human donors into groups of otherwise identical germfree mice and measure drug pharmacokinetics in these animals. Using methods we've developed to capture the majority of an individual's gut microbial community in personalized culture collections, we will test the associations between community composition and drug metabolism by re-building these communities, in whole or in parts, in germfree mice. We will apply these approaches to understand why drugs commonly used for ulcerative colitis are ineffective for 35% of patients despite compelling evidence implicating gut microbes in both drug activation and inactivation. These new experimental approaches for elucidating how differences in personal microbiomes influence drug metabolism will also be applicable for measuring the impact of interpersonal microbial differences on other human traits including predisposition to disease and infection, and even behavior. Public Health Relevance: Previous studies examining the mechanisms underlying individual variations in drug response have focused on linking human genetic polymorphisms with differences in therapeutic efficacy. However, interpersonal differences in the enormous communities of microbes that inhabit the human gut have been almost entirely ignored as a factor in determining individual response to drug therapy. This research will establish a new experimental approach to separate the effects of human and microbial variation in drug metabolism and apply this strategy to understand why commonly used drugs for ulcerative colitis fail 35% of patients.